Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
J Immunother Cancer. 2021 May;9(5). doi: 10.1136/jitc-2020-001942.
This study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.
Three cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.
Based on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05).
The CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.
本研究旨在筛选浆细胞游离 DNA（cfDNA）中的潜在生物标志物，以预测晚期肝胆癌患者接受免疫检查点抑制剂（ICI）治疗的临床结局。
本研究纳入了来自北京协和医学院医院临床试验的 187 例肝胆癌患者，共分为三组。43 例患者接受 PD-1 抑制剂联合仑伐替尼（ICI 队列 1）治疗，108 例患者接受 ICI 治疗（ICI 队列 2），36 例患者接受非 ICI 治疗（非 ICI 队列）。采用癌症基因靶向二代测序panel 评估血浆 cfDNA 和血细胞 DNA 突变谱，以鉴定疗效相关的生物标志物。
基于血浆 cfDNA 的拷贝数变异（CNVs），采用最小绝对收缩和选择算子 Cox 回归方法构建 CNV 风险评分模型，以预测生存情况。两项独立的 ICI 治疗队列的结果表明，CNV 风险评分较低的患者总生存期（OS）和无进展生存期（PFS）均长于评分较高的患者（log-rank p<0.01）。在非 ICI 队列中，CNV 风险评分与 PFS 或 OS 均无相关性。此外，结果表明低 CNV 风险评分患者中有 53%的患者获得了持久的临床获益，而高 CNV 风险评分患者中则有 88%的患者无法从联合治疗中获益（p<0.05）。
血浆 cfDNA 中的 CNVs 可预测 PD-1 抑制剂联合仑伐替尼以及其他 ICI 治疗肝胆癌的联合治疗的临床结局。
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